Parathyroid hormone-related protein (PTHrP), a tumor-derived small polypeptide, plays key roles in cancer cachexia. Our recent work demonstrated that PTHrP stimulates energy expenditure in fat tissues and atrophy in skeletal muscle. Plasma PTHrP was found to be elevated in a group of cancer patients who also displayed features of reduced lean body mass and increased energy expenditure. Neutralization of PTHrP in tumor- bearing mice halts wasting of both adipose tissue and skeletal muscle. This project aims at understanding the mechanisms underlying fat and muscle wasting driven by PTHrP. We predict that the effects of PTHrP are mediated by the PTH/PTHrP receptor. (Aim 1) We propose to deplete this receptor in fat tissue and skeletal muscle of mice and examine molecular and metabolic aspects of wasting induced by tumor-derived PTHrP. We will investigate mechanisms behind hypermetabolism, including adipose tissue browning and altered circadian rhythms. We want to expand our work to different cachexia models and demonstrate importance of the PTHrP pathway across different tumor types. We also predict that PTHrP stimulates skeletal muscle atrophy in collaboration with other tumor-derived factors. (Aim 2) Using cell-based assays and combining gene expression analysis with proteomics, we identified Colony Stimulating Factor-1 (CSF-1) as a key contributor to PTHrP-driven muscle atrophy. We will study roles of CSF-1 in cancer cachexia and examine its interaction with the PTHrP signaling. Defining a role for the PTH/PTHrP signaling in wasting and identifying novel players in muscle atrophy will greatly expand our understanding of cancer cachexia and may lead to discovery of new ways of therapy. Early experiments proposed for both aims, including initial characterization of the knockout mice and characterization of the CSF-1 pathway in muscle atrophy, will be performed during the mentored phase of this award. The candidate, Dr. Serkan Kir, has a strong research background in cancer and molecular metabolism fields. The proposed research will be conducted in the laboratory of Dr. Bruce Spiegelman at Dana-Farber Cancer Institute and Harvard Medical School. The career development activities to improve candidate's skills will include attending scientific meetings and career workshops, learning new techniques and the support of his scientific advisory committee. The candidate's career goal is to become an independent academic researcher. Long term research goals include understanding molecular and metabolic aspects and temporal evolution of tumor-host interactions and discovering means to prevent tumor growth and its detrimental effects on host metabolism.